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Here, we develop an anatomically grounded framework that systematically evaluates pharmaceutical diffusion within the central nervous system (CNS).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A finite element (FE) model was developed with DS explicitly represented as impermeable obstructions in the extracellular space (ECS) \u2013 consistent with structural remodeling observed in Alzheimer\u2019s disease (AD). The model was calibrated by reproducing experimental diffusion timescales and subsequently applied to quantify the geometric contribution of DS to pharmaceutical transport.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Transport hindrance exhibited a strong dependence on molecular size. Within a representative ECS unit, the arrival of the\n                      <jats:inline-formula>\n                        <jats:alternatives>\n                          <jats:tex-math>$$0.5c_0$$<\/jats:tex-math>\n                          <mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                            <mml:mrow>\n                              <mml:mn>0.5<\/mml:mn>\n                              <mml:msub>\n                                <mml:mi>c<\/mml:mi>\n                                <mml:mn>0<\/mml:mn>\n                              <\/mml:msub>\n                            <\/mml:mrow>\n                          <\/mml:math>\n                        <\/jats:alternatives>\n                      <\/jats:inline-formula>\n                      concentration contour at the venule was delayed by 11 s for Memantine, 14 s for Donepezil, and 80 s for Aducanumab. Spatial analyses revealed penetration delays that were not captured by domain-averaged uptake metrics. A P\u00e9clet number analysis confirmed that ECS transport for all three compounds remains diffusion-dominated under neurodegenerative conditions.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The proposed framework provides a computationally efficient foundation for predictive multiphysics modeling in the human CNS and demonstrates how local ECS obstructions can lead to therapeutic hindrance in AD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s11095-026-04129-w","type":"journal-article","created":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T20:53:11Z","timestamp":1781038391000},"page":"2683-2699","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Dead-Space Microdomains as Explicit Barriers to Extracellular Drug Transport in Alzheimer\u2019s Disease"],"prefix":"10.1007","volume":"43","author":[{"given":"Dimitrios","family":"Charemis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitrios","family":"Lampropoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yannis","family":"Dimakopoulos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Sivolapenko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6055-5775","authenticated-orcid":false,"given":"Maria","family":"Hadjinicolaou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"4129_CR1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2022.105981","volume":"177","author":"J T\u00f8nnesen","year":"2023","unstructured":"T\u00f8nnesen J, Hrab\u0115tov\u00e1 S, Soria FN. 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